![[Feedback]](/icons/banner/feedbackACT.gif){kind=icon}
![[For Subscribers]](/icons/banner/subscriberACT.gif){kind=icon}
![[Archive]](/icons/banner/archiveACT.gif){kind=icon}
![[Search]](/icons/banner/searchACT.gif){kind=icon}
![[Contents]](/icons/banner/tocACT.gif){kind=icon}
|
|
|
|
|
||
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Center for Environmental Genetics and Department of Environmental Health, University of Cincinnati Medical Center, Cincinnati, Ohio
Complex mixtures of carcinogenic metalloids, such as arsenic, and polycyclic aromatic hydrocarbons or halogenated aromatic hydrocarbons are common environmental contaminants. The biological consequences of exposure to these mixtures are unpredictable and, although the health effects of individual chemicals may be known, the toxicity of environmental mixtures is largely unexplored. Arsenic, not a potent mutagen by itself, is co-mutagenic with many DNA-damaging agents. Mixtures of arsenite plus benzo[a]pyrene (B[a]P) augment B[a]P mutagenicity, suggesting that arsenite might uncouple expression of phase I and II genes responsible for detoxification. We have studied the effects of arsenite exposure on the activation of the aryl hydrocarbon receptor (AHR) and its subsequent role in gene transactivation. Treatment of mouse Hepa-1 cells with arsenite induces AHR nuclear translocation and binding to the Cyp1a1 gene promoter with the same efficiency as tetrachlorodibenzo-p-dioxin (TCDD), the most potent ligand of the AHR; however, TCDD and B[a]P are an order of magnitude more potent than arsenite in up-regulating Cyp1a1 transcription. Global profiling analyses of cells treated with arsenite plus B[a]P indicate that several phase I and II detoxification genes are in some cases additively and in others synergistically deregulated by the mixtures. Real-time reverse transcription-polymerase chain reaction analyses of mouse embryonic fibroblasts showed that the mixtures had an additive effect on the mRNA levels of Cyp1b1, a prototypical phase I detoxification gene, and an AHR-dependent synergistic effect on the corresponding levels of Nqo1, a prototypical phase II gene. We conclude that exposure to arsenite/B[a]P mixtures causes regulatory changes in the expression of detoxification genes that ultimately affect the metabolic activation and disposition of toxicants.
This article has been cited by other articles:
|
|
 |
|
  J.-P. Wu, L. W. Chang, H.-T. Yao, H. Chang, H.-T. Tsai, M.-H. Tsai, T.-K. Yeh, and P. Lin Involvement of Oxidative Stress and Activation of Aryl Hydrocarbon Receptor in Elevation of CYP1A1 Expression and Activity in Lung Cells and Tissues by Arsenic: An In Vitro and In Vivo Study Toxicol. Sci., February 1, 2009; 107(2): 385 - 393. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Y. C. M. Staal, D. S. Pushparajah, M. H. M. van Herwijnen, R. W. H. Gottschalk, L. M. Maas, C. Ioannides, F. J. van Schooten, and J. H. M. van Delft Interactions between polycyclic aromatic hydrocarbons in binary mixtures: Effects on gene expression and DNA adduct formation in precision-cut rat liver slices Mutagenesis, November 1, 2008; 23(6): 491 - 499. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 X. Chang, Y. Fan, S. Karyala, S. Schwemberger, C. R. Tomlinson, M. A. Sartor, and A. Puga Ligand-Independent Regulation of Transforming Growth Factor {beta}1 Expression and Cell Cycle Progression by the Aryl Hydrocarbon Receptor Mol. Cell. Biol., September 1, 2007; 27(17): 6127 - 6139. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. M. Korashy and A. O. S. El-Kadi Regulatory Mechanisms Modulating the Expression of Cytochrome P450 1A1 Gene by Heavy Metals Toxicol. Sci., November 1, 2005; 88(1): 39 - 51. [Abstract] [Full Text] [PDF]
|
|
 |
 |
 |
|
 |
 |
 |
